AK104 declares to go on the market!

Recently, China's anti-biological field has frequently been positive

On August 19, BeiGene announced that Blincyto (Blincyto) was officially commercialized and launched, and it will cover 83 pharmacies in 62 cities across the country

Coincidentally, on August 24, Kangfang Bio announced that CDE had agreed to the company's submission of a new drug application for Cadonilimab (AK104, PD-1×CTLA4) for the treatment of recurrent or metastatic cervical cancer, and gave priority review qualifications

And another leading double-antibody, Corning Jerry, also released a blockbuster news, CSPC subsidiary Jinmante Biotechnology obtained KN026 as a single drug and combined with KN046 to treat breast cancer and gastric cancer indications in mainland China for the exclusive development and commercialization Corning Jerry will have the right to receive up to 1 billion yuan in advance and milestone fees

At present, four dual-antibody drugs have been approved for marketing in the world, including catumaxomab (CD3×EpCAM, delisted), belintuzumab (CD3×CD19), and imeticizumab (FIX× FX) and Rybrevant (EGFR×cMet)

Blincyto

Belintoomab is a bispecific CD19-directed CD3 T cell adapter molecule with a molecular weight of only 55KDa.

Image: Blincyto

The design of Blincyto is based on Amgen's BiTE platform.

In response to the problem of too short half-life, Amgen further designed the HLE (Half-life Extended) BiTE molecule, which essentially integrates the Fc structure into the BiTE, so that the non-IgG-like double antibody molecule without the Fc end is transformed into the double antibody molecule with the Fc end.

Figure: BiTE and HLE BiTE platforms

In 2014, belintoomab was approved by the FDA for the treatment of relapsed/refractory B-ALL

After the listing of Bellinto Oumab, sales rose rapidly, reaching 379 million U.

my country's dual antibody layout

In the context of global bi-antibody research and development, a number of companies in China are also involved in the research and development of bispecific antibodies

(1) Kangfang Bio is focused on meeting the pending global medical needs in tumor, immune and other therapeutic fields.

AK104 can simultaneously target two verified immune checkpoint molecules: programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and show PD-1 and CTLA- 4 The clinical efficacy of monoclonal antibody combination therapy and the good safety that the combination therapy cannot provide

Picture: AK104 structure

Currently, AK104 being carried out worldwide over ten clinical trials covering indications of cervical cancer, nasopharyngeal carcinoma, gastric cancer, liver cancer

AK112 can recognize and bind immunosuppressive checkpoint molecules PD-1 and vascular endothelial growth factor VEGF at the same time.

(2) Corning Jereh has created a biomacromolecule drug discovery, R&D, and production technology platform with independent intellectual property rights, including a protein/antibody engineering platform, an antibody screening platform, and a multifunctional antibody development platform

KN046 is composed of two different single domain antibodies and an Fc fragment.
The two single domain antibodies target PD-L1 and CTLA-4, respectively
.
From a design perspective, single-domain antibodies are the smallest unit known to bind to the target antigen, and have a stronger potential to penetrate solid tumors
.
In addition, KN046 does not directly bind to the interface between CTLA-4 and B7 ligand, but blocks the binding between CTLA-4 and B7 ligand through the outside of the interface, which is expected to improve the safety of the drug
.
In the WCLC 2021, the median progression-free survival (mPFS) of KN046 in the second-line treatment of NSCLC was 3.
68 months, mOS was not reached, the 6-month OS rate reached 85.
6%, and the 12-month OS rate reached 69.
7%
.
Compared with PD-1/PD-L1 inhibitors, the efficacy has obvious advantages
.

Figure: KN046 mechanism of action

KN026 is a HER2×HER2 bispecific antibody.
The basic sequences of the two heavy chains are derived from trastuzumab and pertuzumab.
It can simultaneously bind to two non-overlapping epitopes D2 and D4 of HER2
.
At ASCO in 2020, Corning Jereh disclosed the phase I clinical data of KN026.
The trial included 62 breast cancer patients who had previously received trastuzumab.
The ORR of KN026 treatment reached 29% (17/62), and the DCR reached 74.
2.
%(46/62)
.
In terms of safety, KN026 grade 3 and above TEAE reached 6.
45%, including hypertension and elevated transaminase
.

summary

In recent years, China's innovative drug research and development has ushered in a new climax
.
Under the leadership of leading companies such as Kangfang Bio, Corning Jereh, BeiGene, and other leading companies, the research and development of dual-antibody drugs presents a lively scene of competition among thousands of sails and competition among hundreds of horses
.
According to incomplete statistics, there are more than 40 companies deploying dual-antibody drugs in China
.
But behind the excitement, we must be wary of excessive drug development, especially the clustering of targets
.
Taking the CD3×CD19 target as an example, in addition to the Blincyto introduced by BeiGene, companies such as Jiannenglong and Lvzhu Biology have also deployed this target combination
.
In addition, the CD19 CAR-T represented by Kymriah and Yescarta, and the CD19 ADC represented by Zynlonta will also intensify the competition on this track in the future
.
Therefore, behind the "lively" R&D, the competition of R&D speed, the selection of targets and the layout of commercialization are the key points that innovative pharmaceutical companies must pay attention to
.